The past 5 years has been the most productive epoch in my career. I supported my salary with an NIAAA Independent Investigator (KO2) Award that markedly reduced my clinical and administrative responsibilities. Consequently, since 1998, I published 128 research papers and reviews including the multicenter VA naltrexone alcohol dependence study, characterization of NMDA receptor function alterations with alcohol dependence and the familial risk for alcoholism, completion of studies exploring roles for glutamate receptor antagonist or glutamate release inhibiting drugs for treating alcohol dependent patients, and completion of an initial characterization of time-dependent changes in the regulation of GABA systems in patients using concurrent measurements of cortical GABA levels with 1H-magnetic resonance spectroscopy (MRS) and GABAA receptor regulation with single photon emission computerized tomography (SPECT). For this work, I received several awards including the Joel Elkes Award (ACNP) and the Hans-Jonas Weitbrecht Scientific Award (Bayer). During this period, I renewed our VA Alcohol Research Center, led the establishment of the NIAAA Center for the Translational Neuroscience of Alcoholism (CTNA), and received funding for two RO 1 grants and a VA Merit Review Grant. I also participated in several national and international committees, served on the Editorial Boards of several journals, and mentored several highly accomplished trainees. Over the next five years, I propose to advance the scientific theme of my KO2 Award: to further characterize alterations in amino acid neurotransmission associated with alcohol dependence. The principal new conceptual and educational focus of this application is to unite psychopharmacologic and neuroimaging techniques that were my focus for the past five years with molecular genetic (candidate gene) and molecular neuroscientific (mRNA expression arrays) techniques that may help to add significant explanatory power to the proposed studies. I also propose to characterize the specificity of alterations in glutamatergic and GABAergic alterations associated with the vulnerability to alcohol dependence by comparing ethanol, sodium pentothal (barbiturate), and ketamine (NMDA receptor antagonist) responses in healthy individuals with and without family histories of ethanol dependence.